Process for the treatment of hyperuricemia

ABSTRACT

PROCESS FOR THE TREATMENT OF HYDPERURICEMIA WHICH COMPRISES ADMINISTERING A COMPOUND OF THE FORMULA   2-(R&#39;&#39;-N(-R&#34;)-(CH2)2-CO-)-2,3-DIHYDROBENZOFURAN   IN WHICH R&#39;&#39; AND R&#34; EACH REPRESENT AN ALKYL GROUP CONTAINING 1 TO 5 CARBON ATOMS OR TOGETHER WITH THE NITROGEN ATOM FORM A HETEROCYCLIC RING; OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF.

3,830,929 PROCESS FOR THE TREATMENT OF HYPERURICEMIA Joseph Nordmann,Paris, Georges Dominique Mattioda, Enghien-les-Baius, Robert AlexandreAntoine Faure, Paris, and Gerard Paul Marie Henri Loiseau, Sceaux,France, assignors to Produits Chimiques Ugine Kuhlmann, Paris, France NoDrawing. Filed Apr. 11, 1973, Ser. No. 350,228 Int. Cl. A61k 27/00 US.Cl. 424-285 6 Claims ABSTRACT OF THE DISCLOSURE Process for thetreatment of hyperuricemia which comprises administering a compound ofthe formula in which R and R" each represent an alkyl group containing 1to carbon atoms or together with the nitrogen atom form a heterocyclicring; or a pharmaceutically acceptable salt thereof.

The present invention concerns a process for the treatment ofhyperuricemia.

A certain number of compounds is known of the general formula:

RI oocnlonlN in which R' and R" represent alkyl groups containing 1 to 5carbon atoms, which may be the same or difierent, or form with thenitrogen atom a heterocyclic ring for example the morpholino andpiperidino rings possible containing another hetero-atom.

The compounds of formula (I) may be prepared, for example, by theMannich reaction by condensation of 2- acetyl-benzofuran, in a solventmedium, with formaldehyde or a polymer of formaldehyde and a secondaryamine (A. Burger et al., I. Am. Chem. Soc., 67, 566 (1945), E. B. Knott,J. Chem. Soc., 1190 (1947), F. Binon et al., Chimie therapeutique(1966), 5, 331). The alcohols derived therefrom have been studied fortheir analgesic properties.

It has now been found that the compounds of formula (I) and theirmineral acid salts are inhibitors of xanthineoxidase. Having regard totheir anti-uric action they may be used in human therapeutics, forexample for the treatment of gout and other syndromes connected withhyperuricemia.

The invention is illustrated by the following Examples, in which theparts are parts by weight unless the contrary is mentioned:

EXAMPLE 1 A mixture comprising 32 parts of 2-acetyl-benzofuran, 9 partsof trioxane and 20 parts of dimethylene hydrochloride and 0.4 parts ofacetic acid is heated under reflux for 4 hours. It is then cooled and250 parts by volume of acetone are added, when a crystalline product isprecipitated. It is filtered off, then recrystallised from ethanol and23 parts of 3 N,N dimethylamino-(2)-1-benzofuranyl-l-propanonehydrochloride of melting point 202 C. (Kofier) (literature: 203 C.) arethus obtained.

United States Patent 0 3,830,929 Patented Aug. 20, 1974 PercentageCalculated Found analysis (percent) (percent) 0 61. 53 61. 23 H 6. 35 6.35 N 5. 52 5. 32 Cl 13. 97 13. 38

EXAMPLE 2 0n operating under the conditions described in Example 1, butusing 29.8 parts of piperidine hydrochloride, 25 parts of 3piperidino-(2)-l-benzofuranyl-l-propanone hydrochloride are obtained, ofmelting point 205 C. (Maquenne), literature: 202 C.

EXAMPLE 3 On operating as in Example 1, but with 30.7 parts ofmorpholine hydrochloride, 27 parts of 3-morpholino-(2)-l-benzofuranyl-l-propanone hydrochloride are obtained, of melting point260 C. (Maquenne).

Toxicological and Pharmacological Properties The acute toxicities of theproducts according to the invention, in the form of the hydrochlorides,have been determined on CD 1 mice by intravenous injection and takenorally. The LD 50 are shown in the following Table:

R Cumulative quantal N/ method LD 50, mgJkg.

\ Intra- R" venous Oral Dimethylamin0.- 87 265. Pipen'dino About 400.Morpholino About 525.

Their principal pharmacological property is represented by theiranti-uric action. This property has been able to be shown by theirinhibitive action on the xanthine-oxidase according to the followingrecord:

(1) Preparation of the solution of enzyme A suspension ofxanthine-oxidase in a saturated solution of ammonium sulphate is used;the enzymic activity is about 3 u./ml. 0.1 ml. of this suspension isdissolved in 1 ml. of a buifer solution of pH 7.5.

(2) Preparation of the control experiment without inhibitor To 5 ml. ofa solution of xanthine (38 mg./litre and pH 7.5) are added 0.1 ml. ofthe enzyme solution.

is calculated, which represents the ratio of the rates of conversioninto uric acid of the control test (UT) and the 3 test in presence ofinhibitor (UE), thirty minutes after the beginning of the reaction. Whenthe activity is zero or very weak, the coefiicient A is near 1. -Itbecomes greater as the inhibiting power is increased.

Under these conditions, the coefiicients of activity A are as follows:

R! -N Coeffi- Concencient of R trations activity Dimethylamiuo.. IO- M25 2.10- M 23 4.10-M 7. 7 SAD- M 4. 1

Piperidine. 2.10* M 10 4.10' M 5. 8

Morpholino IO M 18. 4 2.l* M 16. 8 4.10- M 11 Therapeutic Application 4We claim: 1. The process for the treatment of hyperuricemia in a patientwhich comprises administering thereto mg. to 1000 mg. per day of acompound of the formula:

R! C O CHQCHIN in which R and R" each represent an alkyl groupcontaining 1 to 5 carbon atoms; or a pharmaceutically acceptable saltthereof.

2. The process of Claim 1, wherein R and R" are identical to each other.

3. The process of Claim 1, wherein R and R" are different from eachother.

4. The process of Claim 1, wherein the compound is administered inadmixture with a pharmaceutically acceptable carrier.

5. The process of Claim 4, wherein the compound is administered in theform of a compressed tablet, gelatincoated pill cachet or injectableampul.

6. The process of Claim 1 wherein the compound is administered in dosesof 15 mg. to mg.

References Cited J.A.C.S., 67, 566569, (1945).

ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner US.Cl. X.R. 424.-248, 267.

